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WO2024099428A1 - Inhibiteur de fusion membranaire pour inhiber le virus du sida et souche résistante aux médicaments de celui-ci, et son utilisation pharmaceutique - Google Patents

Inhibiteur de fusion membranaire pour inhiber le virus du sida et souche résistante aux médicaments de celui-ci, et son utilisation pharmaceutique Download PDF

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Publication number
WO2024099428A1
WO2024099428A1 PCT/CN2023/130970 CN2023130970W WO2024099428A1 WO 2024099428 A1 WO2024099428 A1 WO 2024099428A1 CN 2023130970 W CN2023130970 W CN 2023130970W WO 2024099428 A1 WO2024099428 A1 WO 2024099428A1
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Prior art keywords
polypeptide
virus
hiv
lipopeptide
cholesterol
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PCT/CN2023/130970
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English (en)
Chinese (zh)
Inventor
何玉先
耿秀珠
朱园美
种辉辉
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National Institute of Pathogen Biology CAMS and PUMC
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National Institute of Pathogen Biology CAMS and PUMC
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Priority to EP23888113.0A priority Critical patent/EP4617282A1/fr
Priority to JP2025527054A priority patent/JP2025537298A/ja
Priority to KR1020257019376A priority patent/KR20250109218A/ko
Priority to AU2023378464A priority patent/AU2023378464A1/en
Publication of WO2024099428A1 publication Critical patent/WO2024099428A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16041—Use of virus, viral particle or viral elements as a vector
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present application belongs to the field of biomedicine and relates to membrane fusion inhibitors for inhibiting HIV and its drug-resistant strains, their derivatives, their pharmaceutical compositions and their pharmaceutical uses.
  • AIDS is caused by infection with the human immunodeficiency virus (HIV), and currently there are approximately 38.4 million people infected worldwide (www.unaids.org). Since an AIDS vaccine has not yet been successfully developed, drugs that block different stages of viral replication play an important role in the treatment and prevention of HIV infection.
  • Clinical therapeutic drugs mainly include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, viral entry inhibitors and integrase inhibitors (www.fda.gov).
  • the widely used highly effective antiviral treatment regimen mainly consists of 3-4 reverse transcriptase inhibitors and protease inhibitors. Due to the persistence of HIV infection, patients need long-term medication, which can easily lead to drug resistance, seriously affecting the clinical treatment effect. Therefore, the development of new anti-HIV drugs has always been a major demand for the prevention and control of AIDS.
  • HIV entry into target cells is mediated by the trimeric envelope glycoprotein (Env) on its surface, which is composed of surface subunit gp120 and transmembrane subunit gp41 connected by non-covalent bonds.
  • Env trimeric envelope glycoprotein
  • gp120 binds to the cell receptor CD4 and auxiliary receptors (such as CCR5 or CXCR4) successively, causing conformational changes in gp120, exposing and activating the membrane fusion function of gp41.
  • the N-terminal fusion peptide (FP) of gp41 is inserted into the target cell membrane, and then the C-terminal helical region (CHR) and the N-terminal helical region (NHR) fold inversely to form a stable hexameric helix (6-HB) structure, which brings the viral membrane and the cell membrane closer for fusion, so that the HIV genome enters the cell and causes infection.
  • CHR C-terminal helical region
  • NHR N-terminal helical region
  • the structure shows that the C-terminus of the NHR helix contains a deep hydrophobic pocket, while the N-terminal sequence of the CHR helix (WMEWDREI) is the pocket-binding domain (PBD), in which two highly conserved tryptophans (W) and one isoleucine (I) inserted into the NHR pocket mediate extensive hydrophobic interactions, which are essential for the formation of 6-HB and viral infection (Chan et al., 1997).
  • PPD pocket-binding domain
  • W tryptophans
  • I isoleucine
  • HIV membrane fusion inhibitors act on the early stages of viral replication and work by blocking the virus from entering target cells, so they have obvious advantages in treatment and prevention.
  • enfuvirtide also known as T20
  • T20 is a 36-amino acid polypeptide derived from the viral CHR without a PBD sequence. It exerts an antiviral effect by competing with NHR to block the formation of viral 6-HB. Because T20 inhibits viral activity
  • the drug has a relatively low biological half-life, requires large daily doses, and is prone to induce drug resistance. Its clinical application is widely restricted. Therefore, the development of new HIV membrane fusion inhibitors has always attracted attention at home and abroad.
  • C34 contains PBD, and the C34 amino acid sequence is considered to be the core sequence of CHR.
  • SFT Serine
  • ABT Abovetac
  • SFT mutates 14 amino acids of C34 and adds serine (S) and glutamic acid (E) at the N-terminus and C-terminus respectively to increase the stability and target binding ability of the peptide.
  • ABT only mutates three amino acids of C34 and connects 3-maleimidopropionic acid (MPA) to the side chain of lysine (K) at position 13 to enable it to bind to serum albumin.
  • MPA 3-maleimidopropionic acid
  • K lysine
  • LP-98 like T20, does not contain the PBD sequence in its molecular structure.
  • the 8 amino acids at the C-terminus of T20 are removed, and 16 of the 28 amino acids retained are mutated to promote the formation of a "salt bridge structure" between E and K amino acids, which significantly improves the stability of the helical structure of the polypeptide; at the same time, LP-98 is modified with cholesterol at the C-terminus through the K side chain to become a lipopeptide.
  • LP-98 in inhibiting a group of replicative HIV strains from infecting different target cells reached an extremely low picomolar (pM) level, which is 273,368 times higher than T20, and 120,789 times and 376,368 times higher than the first-line AIDS drugs zidovudine (AZT) and lamivudine (3TC), respectively.
  • pM picomolar
  • LP-98's activity in inhibiting 36 representative internationally prevalent HIV-1 subtype pseudoviruses is 10,504 times higher than T20 and 3,751 times higher than AZT; low-dose administration of LP-98 has a strong therapeutic and preventive effect in monkey infection models (Xue et al., 2022).
  • the inventors also found that the inhibitory activity of LP-98 against T20-resistant HIV strains was significantly reduced, affecting its drugability.
  • FIG. 1 A schematic diagram of sequence comparison of T20, C34, SFT, ABT and LP-98 is shown in Figure 1 .
  • the technical problem to be solved by this application is how to effectively inhibit HIV and its drug-resistant strains.
  • the present invention aims to develop a new structure HIV membrane fusion inhibitor with super potent, broad spectrum and long-acting effect, so as to realize the huge clinical development value and application prospect. Therefore, the present application provides a membrane fusion inhibitor for inhibiting HIV and its drug-resistant strains, its derivatives, its pharmaceutical composition and its pharmaceutical use.
  • the present application provides a lipopeptide, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof or a derivative thereof.
  • the lipopeptide is a compound represented by structural formula I;
  • Structural formula I X 1 -polypeptide P1-X 2 ;
  • the polypeptide P1 is as follows (a1) or (a2) or (a3):
  • (a2) A polypeptide having antiviral activity obtained by substituting and/or deleting and/or adding amino acid residues based on (a1);
  • (a3) a polypeptide having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to (a1) and having antiviral activity;
  • the terminal amino acid residue of the polypeptide P1 is modified with a lipophilic compound group
  • X1 is the amino terminal protecting group of polypeptide P1;
  • X2 is the carboxyl terminal protecting group of polypeptide P1.
  • X is isoleucine (I), valine (V) or leucine (L).
  • amino acids at positions 2 (X), 9 (I), 16 (A), 23 (N), and 30 (L) in (a1) correspond to the amino acids at position a of the CHR helix
  • amino acids at positions 5 (L), 12 (L), 19 (Q), and 26 (E) in (a1) correspond to the amino acids at position d of the CHR helix.
  • These amino acids at positions a and d are key amino acids for the binding of CHR to the NHR target sequence to form a 6-HB structure, and are relatively conservative in sequence and function and are not easily replaced by other amino acids.
  • amino acids corresponding to other positions of the CHR helix do not or rarely interact directly with the NHR, and are therefore easily replaced by other amino acids without affecting or significantly affecting the antiviral activity of the polypeptide.
  • substitution and/or deletion and/or addition is located at positions other than the following positions in (a1): the 2nd position (X), the 9th position (I), the 16th position (A), the 23rd position (N), the 30th position (L), the 5th position (L), the 12th position (L), the 19th position (Q), and the 26th position (E).
  • the lipopeptide is a compound represented by structural formula II;
  • the polypeptide P2 is as follows (b1) or (b2) or (b3):
  • (b2) A polypeptide having antiviral activity obtained by substituting and/or deleting and/or adding amino acid residues based on (b1);
  • (b3) has at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, A polypeptide with 95%, 96%, 97%, 98% or 99% identity and having antiviral activity;
  • the terminal amino acid residue of the polypeptide P2 is modified with a lipophilic compound group
  • X3 is the amino terminal protecting group of polypeptide P2;
  • X4 is a carboxyl terminal protecting group of polypeptide P2.
  • amino acids at positions 2 (X), 9 (I), 16 (A), 23 (N), and 30 (L) in (b1) correspond to the amino acids at position a of the CHR helix
  • amino acids at positions 5 (L), 12 (L), 19 (Q), and 26 (E) in (b1) correspond to the amino acids at position d of the CHR helix.
  • These amino acids at positions a and d are key amino acids for the binding of CHR to the NHR target sequence to form a 6-HB structure, and are relatively conservative in sequence and function and are not easily replaced by other amino acids.
  • amino acids corresponding to other positions of the CHR helix do not or rarely interact directly with the NHR, and are therefore easily replaced by other amino acids without affecting or not significantly affecting the antiviral activity of the polypeptide.
  • substitution and/or deletion and/or addition is located at positions other than the following positions in (b1): the 2nd position (X), the 9th position (I), the 16th position (A), the 23rd position (N), the 30th position (L), the 5th position (L), the 12th position (L), the 19th position (Q), and the 26th position (E).
  • the lipophilic compound is cholesterol, cholesterol derivatives (for example, cholesterol succinic acid monoester, 2-cholesterol acetate, 2-cholesterol propionic acid, 3-cholesterol propionic acid, 2-cholesterol butyric acid, 2-cholesterol isobutyric acid, 3-cholesterol butyric acid, 3-cholesterol isobutyric acid, 4-cholesterol butyric acid, 2-cholesterol valeric acid, 2-cholesterol isovaleric acid, 3-cholesterol valeric acid, 5-cholesterol valeric acid, 2-cholesterol hexanoic acid, 6-cholesterol hexanoic acid, 2-cholesterol heptanoic acid, 7-cholesterol heptanoic acid, 2-cholesterol octanoic acid, 8-cholesterol octanoic acid, cholesterol bromoacetate), fatty acids containing 8 to 20 carbon atoms (such as octadecanoic acid or palmitic acid), dihydros
  • the lipophilic compound is cholesterol.
  • the lipophilic compound is cholesterol succinate.
  • the lipophilic compound is cholesterol bromoacetate.
  • the lipophilic compound is octadecanoic acid (stearic acid).
  • the lipophilic compound is palmitic acid.
  • the lipophilic compound is dihydrosphingosine.
  • the lipophilic compound is vitamin E.
  • the cholesterol modification of the terminal amino acid residue is achieved by subjecting the side chain amino group of the lysine at the C-terminus of the peptide chain to an amidation reaction.
  • the cholesterol modification of the terminal amino acid residue is achieved by reacting the thiol group of the cysteine side chain at the C-terminus of the peptide chain with cholesteryl bromoacetate.
  • the stearic acid modification of the terminal amino acid residue is achieved by subjecting the side chain amino group of lysine at the C-terminus of the peptide chain to an amidation reaction.
  • the cholesterol is cholesterol succinate monoester, which is used to modify the polypeptide by an amidation reaction with the amino group of the lysine K side chain in the linker.
  • cholesterol bromoacetate as a modified portion of a polypeptide can also be used to modify the polypeptide by a thioether reaction with the sulfhydryl group of the cysteine (C) side chain in the linker.
  • X 1 is any one of acetyl (Ac), amino (NH 2 ), maleyl, succinyl, tert-butyloxycarbonyl or benzyloxy or other hydrophobic groups or macromolecular carrier groups. In certain embodiments, X 1 is acetyl (Ac).
  • X2 is any one of amino ( NH2 ), carboxyl, hydroxyl, amide, tert-butyloxycarbonyl, or other hydrophobic groups or macromolecular carrier groups. In certain embodiments, X2 is amino ( NH2 ).
  • X 3 is any one of acetyl (Ac), amino (NH 2 ), maleyl, succinyl, tert-butyloxycarbonyl or benzyloxy or other hydrophobic groups or macromolecular carrier groups. In certain embodiments, X 3 is acetyl (Ac).
  • X 4 is any one of amino (NH 2 ), carboxyl, hydroxyl, amide, tert-butyloxycarbonyl, or other hydrophobic groups or macromolecular carrier groups. In certain embodiments, X 4 is amino (NH 2 ).
  • polypeptide P1 or polypeptide P2 have well-known meanings in the art.
  • the polypeptides of the present application also include: A is alanine, Q is glutamine, N is asparagine, etc.
  • the amino acids are L-type amino acids, and one or more (such as 2-5, 2-4 or 2-3) of the amino acids in the polypeptide can also be replaced by L-type amino acids with similar chemical properties or with amino acids with D-type conformation, artificially modified amino acids, rare amino acids existing in nature, etc., to improve the bioavailability, stability and/or antiviral activity of the polypeptide.
  • D-type amino acids refer to amino acids corresponding to L-type amino acids that constitute proteins
  • artificially modified amino acids refer to common L-type amino acids that constitute proteins that have been modified by methylation, phosphorylation, etc.
  • rare amino acids existing in nature include uncommon amino acids that constitute proteins and amino acids that do not constitute proteins, such as 5-hydroxylysine, methylhistidine, ⁇ -aminobutyric acid, homoserine, etc.
  • amino acids in the polypeptide may be replaced, added or deleted by one or more other amino acids, and the polypeptide still has the activity of strongly inhibiting HIV.
  • Amino acid substitution refers to the replacement of an amino acid residue at a certain position in the polypeptide sequence by other amino acids, preferably by conservative amino acids;
  • amino acid addition refers to the insertion of other amino acid residues at the N-terminus or C-terminus or a suitable position of the polypeptide sequence, and the inserted amino acid residues may be all or partly adjacent to each other, or not adjacent to each other;
  • amino acid deletion refers to the deletion of one or more amino acid residues in the polypeptide sequence, as long as the polypeptide has the activity of inhibiting HIV.
  • amino acids are divided into acidic amino acids, basic amino acids and neutral amino acids, wherein acidic amino acids refer to E and D (aspartic acid), basic amino acids refer to K, R (arginine) and H (histidine), and neutral amino acids refer to A, L, I, V, C, Y (tyrosine), G (glycine), M (methionine), S (serine), T (threonine), F (phenylalanine), W (tryptophan) and P (proline).
  • acidic amino acids refer to E and D (aspartic acid)
  • basic amino acids refer to K
  • neutral amino acids refer to A, L, I, V, C, Y (tyrosine), G (glycine), M (methionine), S (serine), T (threonine), F (phenylalanine), W (tryptophan) and P (proline).
  • hydrophilic amino acids D, E, H, K, Q, R, S, T
  • hydrophobic amino acids A, F, I, L, M, P, V, W, Y
  • hydrophilic uncharged amino acids are N, Q, S and T
  • aliphatic uncharged amino acids are A, L, I, V and G
  • non-polar uncharged amino acids are C, M and P
  • aromatic amino acids are Y, F and W.
  • amino acids containing alcohol groups are S and T
  • aliphatic amino acids are L, I, V and M
  • cycloalkenyl-related amino acids are F, H, W and Y.
  • polypeptide P1 is as follows (c1) or (c2) or (c3) or (c4) or (c5) or (c6):
  • (c5) A polypeptide having antiviral activity obtained by substituting and/or deleting and/or adding amino acid residues based on any one of the polypeptides described in (c1) to (c4);
  • (c6) A polypeptide that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of the polypeptides of (c1) to (c4) and has antiviral activity.
  • polypeptide P1 is as follows (c1) or (c2) or (c3) or (c4) or (c5):
  • (c4) A polypeptide having antiviral activity obtained by substituting and/or deleting and/or adding amino acid residues based on any one of the polypeptides described in (c1) to (c3);
  • (c5) A polypeptide that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of the polypeptides of (c1) to (c3) and has antiviral activity.
  • polypeptide P1 has the amino acid sequence shown in SEQ ID NO:1, 5 or 6.
  • polypeptide P2 is as follows (d1) or (d2) or (d3) or (d4):
  • (d4) A polypeptide that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of the polypeptides of (d1) to (d2) and has antiviral activity.
  • polypeptide P2 has the amino acid sequence shown in SEQ ID NO:7 or 8.
  • polypeptide P1 or polypeptide P2 The research experience of the inventors' team over the past decade has shown that the sequence identity of polypeptides derived from substitution, addition or deletion of amino acids in a polypeptide (polypeptide P1 or polypeptide P2) can reach about 60%, 70%, 80%, 90% or 95%, but the inhibitors can still have potent antiviral activity.
  • polypeptide which is as follows (a1) or (a2) or (a3):
  • (a2) A polypeptide having antiviral activity obtained by substituting and/or deleting and/or adding amino acid residues based on (a1);
  • (a3) a polypeptide having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to (a1) and having antiviral activity; or
  • polypeptide is as follows (b1) or (b2) or (b3):
  • (b2) A polypeptide having antiviral activity obtained by substituting and/or deleting and/or adding amino acid residues based on (b1);
  • (b3) a polypeptide having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to (b1) and having antiviral activity.
  • polypeptide P1 is as follows (c1) or (c2) or (c3) or (c4) or (c5) or (c6):
  • (c5) A polypeptide having antiviral activity obtained by substituting and/or deleting and/or adding amino acid residues based on any one of the polypeptides described in (c1) to (c4);
  • (c6) A polypeptide that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of the polypeptides of (c1) to (c4) and has antiviral activity.
  • polypeptide is as follows (c1) or (c2) or (c3) or (c4) or (c5):
  • (c4) A polypeptide having antiviral activity obtained by substituting and/or deleting and/or adding amino acid residues based on any one of the polypeptides described in (c1) to (c3);
  • (c5) a polypeptide having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with any of the polypeptides of (c1) to (c3) and having antiviral activity; or
  • polypeptide is as follows (d1) or (d2) or (d3) or (d4):
  • (d3) A polypeptide having antiviral activity obtained by substituting and/or deleting and/or adding amino acid residues based on any one of the polypeptides described in (d1) to (d2);
  • (d4) A polypeptide that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of the polypeptides of (d1) to (d2) and has antiviral activity.
  • amino acid residue substitutions described herein are conservative substitutions.
  • conservative substitution means an amino acid substitution that does not adversely affect or change the essential properties of the protein/polypeptide comprising the amino acid sequence.
  • conservative substitutions can be introduced by standard techniques known in the art such as site-directed mutagenesis and PCR-mediated mutagenesis.
  • Conservative amino acid substitutions include substitutions of amino acid residues with amino acid residues having similar side chains, such as substitutions with residues physically or functionally similar to the corresponding amino acid residues (e.g., having similar size, shape, charge, chemical properties, including the ability to form covalent bonds or hydrogen bonds, etc.). Families of amino acid residues with similar side chains have been defined in the art.
  • amino acids with basic side chains e.g., lysine, arginine, and histidine
  • acidic side chains e.g., aspartic acid, glutamic acid
  • uncharged polar side chains e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan
  • nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
  • beta-branched side chains e.g., threonine, valine, isoleucine
  • aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine.
  • conservative substitutions generally refer to replacing the corresponding amino acid residue with another amino acid residue from the same side chain family. Methods for identifying conservative amino acid substitutions are well known in the art.
  • the lipopeptides described in this application may contain one or more chiral centers, and/or double bonds and structures such as these, and may also exist as stereoisomers, including double bond isomers (such as geometric isomers), optical enantiomers or diastereomers. Accordingly, any chemical structure described herein, whether it contains the above-mentioned similar structures in part or in its entirety, includes all possible enantiomers and diastereomers of the lipopeptide, including any single stereoisomer (such as a single geometric isomer, a single enantiomer or a single diastereomer). Enantiomers) and any mixture of these isomers.
  • Lipopeptides include but are not limited to various optical isomers, racemates and/or other mixtures.
  • a single enantiomer or diastereomer, such as an optically active isomer can be obtained by asymmetric synthesis methods or racemate resolution methods.
  • the resolution of the racemate can be achieved by different methods, such as conventional recrystallization with a reagent that assists resolution, or by chromatographic methods.
  • lipopeptides also include cis and/or trans isomers with double bonds.
  • the lipopeptide described in the present application includes but is not limited to all pharmaceutically acceptable different forms of the lipopeptide. These pharmaceutically acceptable different forms include various pharmaceutically acceptable salts, solvates, hydrates, complexes, chelates, non-covalent complexes, prodrugs based on the above substances, and any mixtures of the above forms.
  • the pharmaceutically acceptable salts referred to in the present application include acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, methanesulfonate, borate, methyl bromide, bromide, methyl nitrate, calcium edetate, methyl sulfate, dextrorotatory camphorsulfonic acid, mucate, carbonate, naphthylsulfonate, chloride, nitrate, clavulanate, N-methylglucosamine, citrate, ammonium salt, dihydrochloride, oleate, ethylenediaminetetraacetate, oxalate, edisulphonic acid Salts, such as hydroxybenzoate, ...
  • salts can be prepared by standard methods, for example by reaction of the free acid with an organic or inorganic base.
  • a basic group such as an amino group
  • acid salts such as hydrochlorides, hydrobromides, acetates, pamoates, etc. can be used as dosage forms;
  • pharmaceutically acceptable esters such as acetates, maleates, chloromethyl trimethylacetate, etc., and esters known in the literature for improving solubility and hydrolyzability can be used as sustained release and prodrug formulations.
  • the present application also provides a conjugate, which comprises the polypeptide described in the present application and a modified portion.
  • the modified portion is optionally connected to the N-terminus or C-terminus of the polypeptide via a linker.
  • the modified portion is a terminal protecting group.
  • the polypeptide terminal protecting group includes an N-terminal protecting group and/or a C-terminal protecting group.
  • the N-terminal protecting group can be any group of acetyl (Ac), amino (NH 2 ), maleyl, succinyl, tert-butyloxycarbonyl, benzyloxy or other hydrophobic groups or macromolecular carrier groups.
  • the C-terminal protecting group can be any group of amino (NH 2 ), carboxyl, hydroxyl, amide, tert-butyloxycarbonyl or other hydrophobic groups or macromolecular carrier groups.
  • the present application also provides an isolated nucleic acid encoding the polypeptide described in the present application.
  • the present application also provides a vector comprising the isolated nucleic acid described in the present application.
  • Vectors that can be used to insert the target polynucleotide are well known in the art, including but not limited to cloning vectors and expression vectors.
  • the vector is, for example, a plasmid, a cosmid, a phage, etc.
  • the application also provides a host cell comprising the isolated nucleic acid and/or the vector described herein.
  • host cells include, but are not limited to, prokaryotic cells such as Escherichia coli cells, and eukaryotic cells such as yeast cells, insect cells, plant cells and animal cells (such as mammalian cells, such as mouse cells, human cells, etc.).
  • the host cell of the present invention can also be a cell line.
  • the present application also provides a polymer, which is as follows (e1) or (e2) or (e3) or (e4) or (e5) or (e6):
  • the multimer is as follows (e1) or (e2) or (e3):
  • the present application also provides a composition comprising the lipopeptide described in the present application, its pharmaceutically acceptable salt, its solvate, its hydrate or its derivative, or the polypeptide, or the conjugate, or the isolated nucleic acid, or the vector, or the host cell, or the multimer.
  • the present application also provides a pharmaceutical composition, which comprises the lipopeptide, its pharmaceutically acceptable salt, its solvate, its hydrate or its derivative, or the polypeptide described in the present application, and optionally further comprises a pharmaceutically acceptable carrier material.
  • the lipopeptide, its pharmaceutically acceptable salt, its solvate, its hydrate or its derivative, or the polypeptide is present in an effective amount for treating a viral infection or a disease caused by a viral infection.
  • the viral infection is an infection caused by a virus selected from the group consisting of HIV, SIV and its resistant strains.
  • the HIV is HIV-1 and/or HIV-2.
  • the HIV is a T20 resistant virus.
  • the HIV is a LP-98 resistant virus. In certain embodiments, the HIV is a LP-40 resistant virus. In certain embodiments, the HIV is a LP-52 resistant virus. In certain embodiments, the HIV is a SC29EK resistant virus. In certain embodiments, the HIV is a SC22EK resistant virus. In certain embodiments, the HIV is a MTSC22 resistant virus. In certain embodiments, the HIV is an SFT resistant virus.
  • the virus infection is caused by a virus selected from the group consisting of T20 resistant virus, LP-40 resistant virus, LP-52 resistant virus, SC29EK resistant virus, SC22EK Infection caused by a virus selected from the group consisting of drug-resistant virus, MTSC22-resistant virus and SFT-resistant virus.
  • the disease caused by the viral infection is AIDS.
  • the present application also provides the use of any of the above lipopeptides or any of the above pharmaceutically acceptable salts or any of the above derivatives or the polymers, which is as follows (f1) or (f2) or (f3) or (f4):
  • the present application also provides a product, comprising any of the above lipopeptides or any of the above pharmaceutically acceptable salts or any of the above derivatives or the polymers; the function of the product is as follows (g1) or (g2):
  • the present application also provides a product, comprising any of the above polypeptides; the function of the product is as follows (g1) or (g2):
  • the product may further comprise a carrier material.
  • the present application also provides the application of the product, which is as follows (g1) or (g2):
  • the present application also provides the product, which is used as a virus membrane fusion inhibitor; or is used for preventing and/or treating diseases caused by viruses.
  • the present application also provides a method for treating and/or preventing virus infection in animals, comprising administering any of the above lipopeptides or any of the above pharmaceutically acceptable salts or any of the above derivatives or polymers to a recipient animal to inhibit virus infection in the animal.
  • the present application also provides a method for treating and/or preventing diseases caused by viruses, which comprises administering an effective amount of any of the above-mentioned lipopeptides or their pharmaceutically acceptable salts or solvates or hydrates or their derivatives or the polypeptides or the polymers or the pharmaceutical compositions to a subject in need.
  • HIV Any of the above mentioned viruses is HIV.
  • the virus is human immunodeficiency virus (HIV) and/or simian immunodeficiency virus (SIV).
  • the virus is selected from HIV, SIV, and drug-resistant strains thereof.
  • the HIV is HIV-1 and/or HIV-2.
  • the HIV is a T20 drug-resistant virus.
  • the HIV is an LP-98 resistant virus.
  • the virus is T20 resistant virus and/or LP-40 resistant virus and/or LP-52 resistant virus and/or SC29EK resistant virus and/or SC22EK resistant virus and/or MTSC22 resistant virus and/or SFT resistant virus.
  • any of the above products can be a drug or a vaccine.
  • the HIV is a T20 resistant virus. In certain embodiments, the HIV is a LP-40 resistant virus. In certain embodiments, the HIV is a LP-52 resistant virus. In certain embodiments, the HIV is a SC29EK resistant virus. In certain embodiments, the HIV is a SC22EK resistant virus. In certain embodiments, the HIV is a MTSC22 resistant virus. In certain embodiments, the HIV is a SFT resistant virus.
  • the animal is a mammal, such as a human.
  • the viral disease is a disease caused by a virus selected from the group consisting of HIV, SIV, and drug-resistant strains thereof.
  • the viral disease is a disease caused by a virus selected from the group consisting of T20 resistant virus, LP-40 resistant virus, LP-52 resistant virus, SC29EK resistant virus, SC22EK resistant virus, MTSC22 resistant virus and SFT resistant virus.
  • the disease caused by a virus is AIDS.
  • the subject is a mammal, such as a human.
  • the lipopeptide of the present application can be directly administered to patients as a drug, or can be mixed with a suitable carrier or excipient and administered to patients to achieve the purpose of treating and/or preventing AIDS infection.
  • the carrier material is preferably a pharmaceutically acceptable carrier material, including but not limited to water-soluble carrier materials (such as polyethylene glycol, polyvinyl pyrrolidone, organic acid, etc.), poorly soluble carrier materials (such as ethyl cellulose, cholesterol stearate, etc.), enteric carrier materials (such as cellulose acetate phthalate and carboxymethyl ethyl cellulose, etc.). Among them, water-soluble carrier materials are preferred.
  • water-soluble carrier materials such as polyethylene glycol, polyvinyl pyrrolidone, organic acid, etc.
  • poorly soluble carrier materials such as ethyl cellulose, cholesterol stearate, etc.
  • enteric carrier materials such as cellulose acetate phthalate and carboxymethyl ethyl cellulose, etc.
  • These materials can be made into a variety of dosage forms, including but not limited to tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, freeze-dried powder injections, etc. It can be a common preparation, a sustained-release preparation, a controlled-release preparation, and various microparticle delivery systems. In order to make a unit dosage form into a tablet, various carriers known in the art can be widely used.
  • carriers include diluents and absorbents, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; wetting agents and binders, such as water, glycerol, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia, gelatin slurry, sodium carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrators, such as dry starch, alginate, agar powder, brown seaweed starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitan fatty acid esters, sodium lauryl sulfate, Methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as
  • the tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
  • coated tablets such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
  • various carriers known in the art can be widely used.
  • Examples of carriers are, for example, diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinyl pyrrolidone, Gelucire, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium lauryl sulfate, methylcellulose, ethylcellulose, etc.
  • various carriers known in the art can be widely used.
  • Examples of carriers are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.
  • an injectable preparation such as a solution, emulsion, freeze-dried powder injection and suspension
  • all diluents commonly used in the art can be used, for example, water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxygenated isostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, etc.
  • an appropriate amount of sodium chloride, glucose or glycerol can be added to the injectable preparation.
  • conventional cosolvents, buffers, pH regulators, etc. can also be added.
  • colorants, preservatives, spices, flavoring agents, sweeteners or other materials can also be added to the pharmaceutical preparation.
  • the above dosage forms can be administered by injection, including subcutaneous injection, intravenous injection, intramuscular injection and intracavitary injection, etc.; cavity administration, such as rectal and vaginal; respiratory tract administration, such as nasal cavity; mucosal administration.
  • the above administration route is preferably injection.
  • the dosage of the lipopeptide or polypeptide of the present application depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight and individual response of the patient or animal, the specific active ingredient used, the route of administration and the number of administrations, etc.
  • the above dosage can be administered in a single dosage form or divided into several, such as two, three or four dosage forms.
  • the lipopeptide or polypeptide of the present application can be used directly alone for the treatment and prevention of AIDS-infected patients, or it can be used in combination with one or more antiviral drugs to achieve the purpose of improving the overall therapeutic effect.
  • antiviral drugs include but are not limited to reverse transcriptase inhibitors, protease inhibitors, invasion inhibitors, integration inhibitors and maturation inhibitors.
  • the above-mentioned reverse transcriptase inhibitors can be one or more of AZT, 3TC, ddI, d4T, ddT, TDF, Abacavir, Nevirapine, Efavirenz, Delavirdine, Azvudine, Ainovirine, etc.;
  • the above-mentioned protease inhibitors can be one or more of Saquinavir mesylate, Idinavir, Ritonavir, Amprenavir, Kaletra and Nelfinavir mesylate;
  • the above-mentioned invasion inhibitors can be one or more of Maraviroc, TAK-779, T20, T2635, Sifuvirtide, Abovirtide, etc.;
  • the above-mentioned integration inhibitors can be one or more of Raltegravir, Dolutegravir and Elvitegravi, etc.
  • the specific effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the patient's age, weight, general health, sex, and diet; the timing of administration of the specific active ingredient employed, the duration of administration, and the severity of the disorder; Route and excretion rate; duration of treatment; drugs used in combination or concurrently with the specific active ingredient employed; and similar factors known in the medical field.
  • the practice in the art is to start the dose of the active ingredient at a level lower than that required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is obtained.
  • the dosage of the agent of the present application for mammals, especially humans can be between 0.001-1000 mg/kg body weight/day, such as between 0.01-100 mg/kg body weight/day, and for example between 0.1-10 mg/kg body weight/day.
  • the lipopeptide of the present application has extremely strong inhibitory activity against HIV-1, HIV-2 and SIV, and especially significantly improves the inhibitory activity against T20 and LP-98 resistant HIV strains. Therefore, the lipopeptide of the present application is a broad-spectrum inhibitor, which can be used for the treatment and prevention of diseases caused by HIV-1, HIV-2 and SIV infection.
  • the present application has great application value for the prevention and treatment of AIDS.
  • lipopeptides containing only the two amino acids EI at the end of the PBD have significantly enhanced antiviral activity, while further addition of the corresponding amino acid motif containing W2 or W1 leads to a gradual decrease in the antiviral activity of the lipopeptide.
  • This important discovery provides innovative ideas and design strategies for the development of new HIV membrane fusion inhibitor drugs.
  • FIG1 is a schematic diagram of sequence comparison of T20, C34, SFT, ABT and LP-98 in the background art.
  • FIG. 2 is a diagram showing the results of Example 2 (sequence structure of lipopeptides and identification of their anti-HIV-1 activity).
  • FIG3 is a graph showing the results of Example 3 (the inhibitory effects of representative lipopeptides on various HIV-1 drug-resistant strains, and the bold numbers in brackets represent the multiple increase in activity compared to LP-98).
  • FIG. 4 is a graph showing the results of Example 4 (inhibitory effects of representative lipopeptides on HIV-2 and SIV).
  • FIG5 is a graph showing the results of Example 5 (helical structural characteristics of representative lipopeptides and their interactions with target sequences; A: ⁇ -helical content of a single lipopeptide inhibitor; B: helical stability of a single lipopeptide inhibitor; C: ⁇ -helical content of a complex of a lipopeptide inhibitor and N42 polypeptide; D: helical stability of a complex of a lipopeptide inhibitor and N42 polypeptide.)
  • Lipopeptide LP-104 contains all 8 PBD amino acids of W 1 EEW 2 EKKI (including 3 NHR pocket insertion amino acids).
  • W1 refers to the first W of PBD from the N-terminal
  • W2 refers to the second W of PBD from the N-terminal
  • Lipopeptide LP-105 (compared to lipopeptide LP-101, the NHR pocket insertion amino acid I was replaced with amino acid V);
  • Lipopeptide LP-106 (compared to lipopeptide LP-101, the NHR pocket insertion amino acid I was replaced with amino acid L);
  • Lipopeptide LP-107 (compared with lipopeptide LP-101, an amino acid K is added to the C-terminus of the peptide chain);
  • Lipopeptide LP-108 (compared with lipopeptide LP-101, an amino acid C is added to the C-terminus of the peptide chain);
  • Lipopeptide LP-109 (compared with lipopeptide LP-101, the C-terminal modification group of the peptide chain is replaced with stearic acid).
  • the cholesterol modification of lipopeptide LP-98, lipopeptide LP-101, lipopeptide LP-102, lipopeptide LP-103, lipopeptide LP-104, lipopeptide LP-105, lipopeptide LP-106 and lipopeptide LP-107 is achieved by amidation reaction of the side chain amino group of lysine at the C-terminus of the peptide chain.
  • the cholesterol modification of lipopeptide LP-108 is achieved by chemically highly selective thioether formation reaction of the thiol group of the cysteine side chain at the C-terminus of the peptide chain and cholesteryl bromoacetate.
  • the amino termini of the ten lipopeptides are all connected to acetyl (Ac) as the amino terminal protecting group, and the carboxyl termini are all connected to amino (NH 2 ) as the carboxyl terminal protecting group.
  • the stearic acid modification of lipopeptide LP-109 is achieved by amidation reaction of the side chain amino group of lysine at the C-terminus of the peptide chain.
  • LP-101 Ac-EIEELEKKIEELLKKAEEQQKKNEEELKKLEK(chol)-NH 2 ;
  • LP-102 Ac-WEQKIEELEKKIEELLKKAEEQQKKNEEELKKLEK(chol)-NH 2 ;
  • LP-103 Ac-WDREIEELEKKIEELLKKAEEQQKKNEEELKKLEK(chol)-NH 2 ;
  • LP-104 Ac-WEEWEKKIEELEKKIEELLKKAEEQQKKNEEELKKLEK(chol)-NH 2 ;
  • LP-105 Ac-EVEELEKKIEELLKKAEEQQKKNEEELKKLEK(chol)-NH 2 ;
  • LP-106 Ac-ELEELEKKIEELLKKAEEQQKKNEEELKKLEK(chol)-NH 2 ;
  • LP-107 Ac-EIEELEKKIEELLKKAEEQQKKNEEELKKLEKK(chol)-NH 2 ;
  • LP-108 Ac-EIEELEKKIEELLKKAEEQQKKNEEELKKLEKC(chol)-NH 2 ;
  • LP-109 Ac-EIEELEKKIEELLKKAEEQQKKNEEELKKLEKC(C18)-NH 2 .
  • chol means that the C-terminal amino acid is modified with cholesterol, such as cholesterol succinate or cholesterol bromoacetate.
  • (C18) means that the amino group at the C-terminus is modified with stearic acid.
  • amino acid sequences of the polypeptide chains of the ten lipopeptides are as follows (from N-terminus to C-terminus):
  • LP-98 (sequence 10): YEQKIEELLKKAEEQQKKNEEELKKLEK;
  • LP-101 (sequence 1): EIEELEKKIEELLKKAEEQQKKNEEELKKLEK;
  • LP-102 (sequence 2): WEQKIEELEKKIEELLKKAEEQQKKNEEELKKLEK;
  • LP-103 (sequence 3): WDREIEELEKKIEELLKKAEEQQKKNEEELKKLEK;
  • LP-104 (sequence 4): WEEWEKKIEELEKKIEELLKKAEEQQKKNEEELKKLEK;
  • LP-105 (sequence 5): EVEELEKKIEELLKKAEEQQKKNEEELKKLEK;
  • LP-106 (sequence 6): ELEELEKKIEELLKKAEEQQKKNEEELKKLEK;
  • LP-107 (sequence 7): EIEELEKKIEELLKKAEEQQKKNEEELKKLEKK;
  • LP-108 (sequence 8): EIEELEKKIEELLKKAEEQQKKNEEELKKLEKC;
  • LP-109 (sequence 9): EIEELEKKIEELLKKAEEQQKKNEEELKKLEKC.
  • Lipopeptides can be prepared by any conventional method in the prior art.
  • the protected amino acid raw materials used in the peptide synthesis process include Fmoc-Lys(Dde)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Gln(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Val-OH, Fmoc-Cys(Trt)-OH, and Fmoc-Tyr(tBu)-OH.
  • Fmoc is 9-fluorenylmethoxycarbonyl
  • Dde is 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl
  • Boc is tert-butyloxycarbonyl
  • tBu is tert-butyl
  • OtBu is tert-butoxy
  • Trt is trityl
  • Pbf is (2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5-yl)sulfonyl.
  • Rink Amide MBHA resin was used as the carrier resin, and the peptide resin was prepared by coupling with the corresponding protected amino acids in the polypeptide amino acid sequence through Fmoc removal and coupling reaction.
  • the activated first protected amino acid solution is added to the Fmoc-free resin, and the coupling reaction is carried out for 60 minutes.
  • the resin containing the first protected amino acid Fmoc-Lys (Dde) or Fmoc-Cys (Trt) -OH is obtained by filtering and washing.
  • the method for cholesterol accession to the cysteine side chain is based on the literature published by Dwyer et al. (Dwyer et al., 2007). This method has been routinely used in the inventor's laboratory to prepare cholesterol-modified lipopeptides, such as C34-Chol, LP-83, LP-86 and LP-97 (Xue et al., 2022; Zhu et al., 2019).
  • cholesterol bromoacetate is synthesized according to the technical route described in the literature, and then the sulfhydryl group of the cysteine side chain at the C-terminus of the polypeptide and cholesterol bromoacetate are chemically highly selectively grafted to the polypeptide chain by forming a thioether, that is, after the crude polypeptide is synthesized according to the conventional method, it is dissolved in pure DMSO, 1 equivalent of cholesterol bromoacetate dissolved in a small amount of trifluoroacetic acid (THF) is added, and then pure diisopropylethylamine (DIEA) is added to adjust to alkalinity.
  • THF trifluoroacetic acid
  • DIEA diisopropylethylamine
  • step (1) Take 0.3 mmol of stearoyl chloride and 0.6 mmol of DIEA and dissolve them in an appropriate amount of DMF. Slowly add them to the de-Dde resin obtained in step (1). Oscillate the reaction at room temperature for 60 minutes. Filter, wash and dry to obtain the peptide resin.
  • the trifluoroacetate peptide pure product was redissolved with water and acetonitrile, and a large amount of anion exchange resin (acetate form) was added and stirred for 3 hours. After filtering and washing the ion exchange resin with a water/acetonitrile mixed solvent, the filtrate was combined and freeze-dried to obtain a fluffy peptide acetate pure product.
  • the chemical structure of the synthesized lipopeptides was characterized by MALDI-TOF mass spectrometry, and its purity was determined by analytical HPLC (Agela C18-4.6 ⁇ 250mm, flow rate 1mL per minute). The results showed that the purity of the synthesized lipopeptides was greater than 95%.
  • This example uses the HIV pseudovirus system to identify the anti-HIV activity of the new structure lipopeptide, and uses the lipopeptide LP-98 as a control for the new structure lipopeptide to conceptually verify the superiority of the new structure lipopeptide.
  • lipopeptide LP-101 lipopeptide LP-102, lipopeptide LP-103, lipopeptide LP-104, lipopeptide LP-105, lipopeptide LP-106, lipopeptide LP-107, lipopeptide LP-108, LP-109 or lipopeptide LP-98 prepared in Example 1.
  • HIV-1JRFL Env expression vector and backbone plasmid (pSG3 ⁇ env) and TZM-bl cells (TZM-bl cells) are described in the following literature: Xue, J., Chong, H., Zhu, Y., Zhang, J., Tong, L., Lu, J., Chen, T., Cong, Z., Wei, Q., He, Y., 2022. Efficient treatment and pre-exposure prophylaxis in rhesus macaques by an HIV fusion-inhibitory lipopeptide. Cell 185, 131-144e118.
  • HIV-1JRFL Env expression vector and backbone plasmid were co-transfected into HEK293T cells, and then cultured in a 37°C, 5% CO2 cell culture incubator for 48 hours, and then the supernatant was collected, filtered and the filtrate was collected, which was the virus liquid containing HIV-1JRFL pseudovirus particles (called HIV-1JRFL virus liquid), and stored at -80°C for future use.
  • HIV-1NL4-3 virus liquid is a virus liquid containing HIV-1NL4-3 pseudovirus particles.
  • the preparation method is basically the same as the preparation method of HIV-1JRFL virus liquid, and the only difference is that it is replaced with HIV-1NL4-3Env expression vector.
  • HIV-1NL4-3 pseudovirus (“HIV-1NL4-3" in the literature) is recorded in the following literature: Xue, J., Chong, H., Zhu, Y., Zhang, J., Tong, L., Lu, J., Chen, T., Cong, Z., Wei, Q., He, Y., 2022. Efficient treatment and pre-exposure prophylaxis in rhesus macaques by an HIV fusion-inhibitory lipopeptide. Cell 185, 131-144e118.
  • Test virus solution HIV-1NL4-3 virus solution or HIV-1JRFL virus solution.
  • test lipopeptide 1. Dissolve the test lipopeptide in deionized water, and then dilute it with DMEM medium (3-fold dilution) to obtain lipopeptide dilution solution. Set 9 dilutions for each test lipopeptide.
  • test virus solution 50 ⁇ L/well, virus content of 100 TCID50
  • step 3 After completing step 3, add TZM-b1 cell suspension (100 ⁇ L/well) to the 96-well plate and culture in a cell culture incubator at 37° C. and 5% CO 2 for 48 hours.
  • Preparation method of TZM-b1 cell suspension resuspend TZM-b1 cells in DMEM medium and add DEAE-dextran to make the cell concentration be 10 ⁇ 10 4 cells/mL and the DEAE-dextran concentration be 15 ⁇ g/mL.
  • step 4 discard the cell culture supernatant, add cell lysis solution (30 ⁇ L/well), lyse at room temperature for 15 minutes, then add luciferase detection substrate reagent, measure the relative fluorescence unit (RLU) with a microplate photometer, make an inhibition rate curve and calculate the drug half-inhibitory concentration (IC 50 ).
  • cell lysis solution (30 ⁇ L/well)
  • luciferase detection substrate reagent measure the relative fluorescence unit (RLU) with a microplate photometer
  • Luciferase assay substrate reagent Promega, catalog number E1501.
  • Lipopeptide LP-101 can strongly inhibit the infection of HIV-1 NL4-3 pseudovirus and HIV-1JRFL pseudovirus in TZM-b1 cells, with average IC50 values of 0.46pM and 2.26pM, respectively.
  • the average IC50 values of lipopeptide LP-98 used as a control for inhibiting HIV-1 NL4-3 pseudovirus and HIV-1 JRFL pseudovirus were 1.07pM and 2.58pM, respectively.
  • lipopeptide LP-102, lipopeptide LP-103 and lipopeptide LP-104 decreased significantly, especially the IC 50 of lipopeptide LP-104 containing a complete PBD sequence of 8 amino acids inhibiting HIV-1 NL4-3 pseudovirus and HIV-1 JRFL pseudovirus were 14.50pM and 60.18pM, respectively, which were about 32 times and 27 times lower than the activity of lipopeptide LP-101.
  • the results showed that the lipopeptide containing the two amino acids EI at the end of PBD had the highest antiviral activity, while the lipopeptide containing more PBD sequences led to a significant decrease in activity, revealing the relationship between the structure and function of lipopeptide inhibitors.
  • Lipopeptide LP-105 and LP-106 showed inhibitory activity similar to that of lipopeptide LP-101, indicating that amino acid I inserted into the NHR hydrophobic pocket of the lipopeptide can be replaced by amino acid V or L without affecting the activity of the inhibitor.
  • Lipopeptide LP-107 and LP-108 also showed inhibitory activity similar to that of lipopeptide LP-101, indicating that different cholesterol modification methods had no significant effect on the antiviral effect of the inhibitors.
  • This example uses an HIV pseudovirus system to evaluate the inhibitory activity of new structural lipopeptides (using lipopeptide LP-101 and lipopeptide LP-108 as examples) against a variety of HIV membrane fusion inhibitor-resistant virus strains, and uses lipopeptide LP-98 as a control for the new structural lipopeptide to confirm the drugability of the new structural lipopeptide.
  • the T20-resistant NL4-3 mutant is a T20-induced HIV-1 NL4-3 virus mutant, specifically the following mutations Strains: I37T, V38A, V38M, Q40H, N43K, D36S/V38M, I37T/N43K, V38A/N42T.
  • HIV-1 NL4-3 virus HIV-1 NL4-3 WT in the literature
  • the above mutants are all recorded in the following literature (Table 3 in the literature): Chong, H., Yao, X., Zhang, C., Cai, L., Cui, S., Wang, Y., He, Y., 2012. Biophysical property and broad anti-HIV activity of albuvirtide, a 3-maleimimidopropionic acid-modified peptide fusion inhibitor.
  • PloS one 7, e32599.
  • LP-40-induced NL4-3 drug-resistant strains are mutant strains of HIV-1 NL4-3 virus induced by LP-40, specifically the following mutant strains: L33S, V38T, N42T, L33S/I37T, L33S/V38A/N42T.
  • HIV-1 NL4-3 virus (Pseudo virus NL4-3 in the literature) and the above-mentioned mutant strains are recorded in the following literature (located in Table 2 and Table 3 of the literature): Hu, Y., Yu, W., Geng, X., Zhu, Y., Chong, H., He, Y., 2022.
  • LP-52-induced SIVmac239 resistant strains are mutant strains of SIVmac239 virus induced by LP-52, specifically the following mutant strains: V562A, V562M, V562A/E657G, V562M/E657G, V562A/S760G, V562M/S760G.
  • SIVmac239 virus (“Pseudovirus SIVmac239WT” in the literature) and the above-mentioned mutant strains are recorded in the following literature (located in Table 2 of the literature): Yu, D., Xue, J., Wei, H., Cong, Z., Chen, T., Zhu, Y., Chong, H., Wei, Q., Qin, C., He, Y., 2020. Therapeutic Efficacy and Resistance Selection of a Lipopeptide Fusion Inhibitor in Simian Immunodeficiency Virus-Infected Rhesus Macaques. Journal of virology 94, e00384-00320.
  • LP-52-induced NL4-3 drug-resistant strains are mutant strains of HIV-1 NL4-3 virus induced by LP-52, specifically the following mutant strains: V547A/E646G, V547M/646G.
  • HIV-1 NL4-3 virus ("Pseudovirus HIV-1 NL4-3 WT" in the literature) and the above-mentioned mutant strains are recorded in the following literature (located in Table 2 of the literature): Yu, D., Xue, J., Wei, H., Cong, Z., Chen, T., Zhu, Y., Chong, H., Wei, Q., Qin, C., He, Y., 2020. Therapeutic Efficacy and Resistance Selection of a Lipopeptide Fusion Inhibitor in Simian Immunodeficiency Virus-Infected Rhesus Macaques. Journal of virology 94, e00384-00320.
  • the SC29EK-induced NL4-3 drug-resistant strain is a mutant strain of the HIV-1 NL4-3 virus induced by SC29EK, specifically the following mutant strains: E49A, N43K/E49A, Q39R/N43K/N126K, and N43K/E49A/N126K.
  • HIV-1 NL4-3 virus HIV-1 NL4-3 Wild type in the literature
  • the above-mentioned mutant strains are recorded in the following literature (located in Table 1 of the literature): Wu, X., Liu, Z., Ding, X., Yu, D., Wei, H., Qin, B., Zhu, Y., Chong, H., Cui, S., He, Y., 2018. Mechanism of HIV-1 Resistance to an Electronically Constrained alpha-Helical Peptide Membrane Fusion Inhibitor. Journal of virology 92, e02044-02017.
  • SC22EK-induced NL4-3 drug-resistant strains are mutant strains of HIV-1 NL4-3 virus induced by SC22EK, specifically the following mutant strains: E49K, N126K, E49K/N126K.
  • HIV-1 NL4-3 virus (HIV-1 NL4-3 virus Wild type in the literature) and the above mutant strains are all recorded in the following literature (located in Table 1 of the literature): Su, Y., Chong, H., Qiu, Z., Xiong, S., He, Y., 2015a. Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket. Journal of virology 89, 5801-5811.
  • MTSC22-induced NL4-3 drug-resistant strains are mutant strains of HIV-1 NL4-3 virus induced by MTSC22, specifically the following mutant strains: L57R, E136G, L57R/E136G. HIV-1 NL4-3 virus (HIV-1 NL4-3 Wild type in the literature) and the above mutant strains are all recorded in the following literature (located in Table 1 of the literature): Su, Y., Chong, H., Xiong, S., Qiao, Y., Qiu, Z., He, Y., 2015b. Genetic Pathway of HIV-1 Resistance to Novel Fusion Inhibitors Targeting the Gp41 Pocket. Journal of virology 89, 12467-12479.
  • SFT-induced NL4-3 drug-resistant strains are mutant strains of HIV-1 NL4-3 virus induced by SFT, specifically the following mutant strain: Q52R. HIV-1 NL4-3 virus (HIV-1 NL4-3 virus WT in the literature) and the above mutant strains are recorded in the following literature (located in Table 1 of the literature): Yu, D., Ding, X., Liu, Z., Wu, X., Zhu, Y., Wei, H., Chong, H., Cui, S., He, Y., 2018. Molecular mechanism of HIV-1 resistance to sifuvirtide, a clinical trial-approved membrane fusion inhibitor. The Journal of biological chemistry 293, 12703-12718.
  • Test virus fluids each T20-resistant NL4-3 mutant virus fluid, each LP-40-induced NL4-3 resistant strain virus fluid, each LP-52-induced SIVmac239 resistant strain virus fluid, each LP-52-induced NL4-3 resistant strain virus fluid, each SC29EK-induced NL4-3 resistant strain virus fluid, each SC22EK-induced NL4-3 resistant strain virus fluid, each MTSC22-induced NL4-3 resistant strain virus fluid or SFT-induced NL4-3 resistant strain virus fluid.
  • Test lipopeptides lipopeptide LP-101, lipopeptide LP-108 or lipopeptide LP-98 prepared in Example 1.
  • the method is the same as Example 2.
  • lipopeptide LP-101 increased the inhibitory activity of various T20-resistant NL4-3 mutants by 12 to 131 times, and lipopeptide LP-108 increased the inhibitory activity by 14 to 304 times.
  • lipopeptide LP-101 increased the inhibitory activity of various LP-40-induced NL4-3 resistant strains by 20 to 150 times, and lipopeptide LP-108 increased the inhibitory activity by 9 to 250 times.
  • lipopeptide LP-52 increased the inhibitory activity of various SIVmac239 resistant strains by 71 to 758 times
  • lipopeptide LP-108 increased the inhibitory activity by 147 to 907 times.
  • the inhibitory activity of lipopeptide LP-101 against two LP-52-induced NL4-3-resistant strains was increased by 106 or 46 times
  • that of lipopeptide LP-108 against lipopeptide LP-98 was increased by 95 or 30 times.
  • the inhibitory activity of lipopeptide LP-101 against each SC29EK-induced NL4-3-resistant strain was increased by 5 to 392 times, and that of lipopeptide LP-108 against lipopeptide LP-98 was increased by 4 to 429 times.
  • the inhibitory activity of lipopeptide LP-101 against each SC22EK-induced NL4-3-resistant strain was increased by 3 to 11 times, and that of lipopeptide LP-108 against lipopeptide LP-98 was increased by 1 to 10 times.
  • the IC 50 value of lipopeptide LP-98 was 0.4 to 2 times that of lipopeptide LP-101 and 0.2 to 2 times that of lipopeptide LP-108.
  • the IC 50 value of lipopeptide LP-101 and lipopeptide LP-108 were 0.4 to 2 times that of lipopeptide LP-101 and 0.2 to 2 times that of lipopeptide LP-108.
  • the activity of lipopeptide LP-108 was 3-fold higher than that of lipopeptide LP-98, while that of lipopeptide LP-108 was similar to that of lipopeptide LP-98.
  • Test virus fluid HIV-2 ROD virus fluid, HIV-2 ST virus fluid, SIVmac239 virus fluid or SIV PBJ virus fluid.
  • HIV-2 ROD virus and HIV-2 ST virus are both infectious HIV-2 viruses (Virus type: Replicative).
  • SIVmac239 virus and SIV PBJ virus are both SIV pseudoviruses (Virus type: Pseudotype).
  • HIV-2 ROD virus, HIV-2 ST virus, SIVmac239 virus and SIV PBJ virus are all recorded in the following literature (located in Table S1 of the literature): Xue, J., Chong, H., Zhu, Y., Zhang, J., Tong, L., Lu, J., Chen, T., Cong, Z., Wei, Q., He, Y., 2022. Efficient treatment and pre-exposure prophylaxis in rhesus macaques by an HIV fusion-inhibitory lipopeptide. Cell 185, 131-144e118.
  • Test lipopeptides lipopeptide LP-101, lipopeptide LP-108 or lipopeptide LP-98 prepared in Example 1.
  • the method is the same as Example 2.
  • the secondary structure ( ⁇ -helix content) and thermal stability (Tm value) of the lipopeptides LP-101 and LP-108 prepared in the examples and their complexes with the target sequence were determined by circular dichroism (CD) technology.
  • CD circular dichroism
  • NHR polypeptide The polypeptide N42 corresponding to the NHR sequence of the gp41 fusion protein as a lipopeptide inhibitor mimetic target was synthesized by our laboratory and is commonly used, see the literature published by the inventor (Xue et al., 2022).
  • the polypeptide N42 is: Ac-STMGAASMTLTVQARQLLSGIVQQQQNNLLRAIEAQQHLLQLT-NH 2 , and the amino acid sequence is shown in SEQ ID NO: 11.
  • CD determination method Lipopeptide LP-101, lipopeptide LP-108, lipopeptide LP-98, N42 polypeptide and lipopeptide LP-101
  • a mixture of N42/LP-101, a mixture of N42 polypeptide and lipopeptide LP-108 (N42/LP-108), and a mixture of N42 polypeptide and lipopeptide LP-98 (N42/LP-98) were dissolved in phosphate buffer (PBS) at pH 7.2, respectively, to obtain solutions with a final concentration of 10 ⁇ M for lipopeptide and N42 polypeptide, respectively. Each solution was placed in a 37° C.
  • PBS phosphate buffer
  • a Jasco spectropolarimeter (model J-815) was used to scan the change of the molar ellipticity [ ⁇ ] ⁇ of the solution in the wavelength range of 195-270 nm.
  • a typical ⁇ -helical structure can have maximum negative peaks at 208 nm and 222 nm.
  • the PBS blank control was subtracted to correct the spectrum value.
  • a peak value of -33000 degree.cm 2 .dmol -1 was used as the standard for 100% ⁇ -helical content, and the percentage of the polypeptide ⁇ -helical content was calculated according to the molar ellipticity of the solution at 222 nm.
  • the solution was then added to the corresponding cuvette for thermal stability testing, and the CD temperature control module was adjusted to scan the change of [ ⁇ ]222 of the polypeptide solution with temperature at 2°C per minute from 20 to 98°C.
  • the melting curve was smoothed, and the midpoint temperature (Tm) of the thermal dissociation transition was calculated using Origin software to reflect the thermal stability of the helix.

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Abstract

L'invention concerne un inhibiteur de fusion membranaire pour inhiber le VIH et une souche résistante aux médicaments de celui-ci, un dérivé de celui-ci, une composition pharmaceutique de celui-ci, et une utilisation pharmaceutique de celui-ci.
PCT/CN2023/130970 2022-11-11 2023-11-10 Inhibiteur de fusion membranaire pour inhiber le virus du sida et souche résistante aux médicaments de celui-ci, et son utilisation pharmaceutique Ceased WO2024099428A1 (fr)

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EP23888113.0A EP4617282A1 (fr) 2022-11-11 2023-11-10 Inhibiteur de fusion membranaire pour inhiber le virus du sida et souche résistante aux médicaments de celui-ci, et son utilisation pharmaceutique
JP2025527054A JP2025537298A (ja) 2022-11-11 2023-11-10 エイズウイルスおよびその薬剤耐性株を阻害するための膜融合阻害剤およびその医薬用途
KR1020257019376A KR20250109218A (ko) 2022-11-11 2023-11-10 Aids 바이러스 및 이의 약물-내성 균주를 억제하기 위한 막 융합 억제제, 및 이의 약학적 용도
AU2023378464A AU2023378464A1 (en) 2022-11-11 2023-11-10 Membrane fusion inhibitor for inhibiting aids virus and drug-resistant strain thereof, and pharmaceutical use thereof

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KR20250162880A (ko) * 2023-03-20 2025-11-19 허난 제뉴인 바이오테크 컴퍼니 리미티드 광범위 바이러스 막 융합 억제제, 및 이의 제조 방법 및 이의 용도

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SU, Y.CHONG, H.QIU, Z.XIONG, S.HE, Y.: "Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket", JOURNAL OF VIROLOGY, vol. 89, 2015, pages 5801 - 5811
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YU, D.DING, X.LIU, Z.WU, X.ZHU, Y.WEI, H.CHONG, H.CUI, S.HE, Y.: "Molecular mechanism of HIV-1 resistance to sifuvirtide, a clinical trial-approved membrane fusion inhibitor", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 293, 2018, pages 12703 - 12718
YU, D.XUE, J.WEI, H.CONG, Z.CHEN, T.ZHU, Y.CHONG, H.WEI, Q.QIN, C.HE, Y.: "Therapeutic Efficacy and Resistance Selection of a Lipopeptide Fusion Inhibitor in Simian Immunodeficiency Virus-Infected Rhesus Macaques", JOURNAL OF VIROLOGY, vol. 94, 2020, pages 00384 - 00320
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